Heinz Drexel, MD, FESC, FAHA Department of Medicine and Cardiology &

1. ESC Working Group Meeting „Cardiovascular Pharmacotherapy“ - How to run a trial efficiently, May 29, 2015 The Role of the PI: Keys to Success, Perils and Tribulations Heinz Drexel, MD, FESC, FAHA Department of Medicine and Cardiology & VIVIT Institute at the Academic Teaching Hospital Feldkirch, A Private University of the Principality of Liechtenstein, Triesen, FL Drexel University College of Medicine, Philadelphia, PA, USA

2. Personal Interest and Experience H. Drexel National PI - Dyslipidemia International Study (DYSIS, MSD) - ODYSSEY Outcome Study (Alirocumab, Sanofi-Aventis) • PI of ~ 15 parallel trials • Long-term observationalstudies

3. Prerequisites for becoming trained in trials:the institution • Earlier publications • Sound scientific programme • Ongoing trials • Time offered by the team members • High quality of mentor • Recruitable patients • Cooperation with the clinical unit

4. Stages of development at our institution Acquisition of Competitive Grants Cooperation with Other Centers Molecular Biology Lab Investigator Driven Studies, Recruitment of Large Cohorts Participation in Multicenter Trials 1997 2005 2015

5. OUTLINE What do I want so share with you? • Definition of the PI • Personal experience • Your needs

6. OUTLINE What do I want so share with you? • Definition of the PI • Personal experience • Your needs

7. Definition of the Principal Investigator (PI) A principal investigator (PI) is the lead scientist for a particular well-defined research project, such as a laboratory study or clinical trial. It is often used as a synonym for "head of the laboratory" or "research group leader", not just for a particular study.

8. Role of the Principal Investigator (PI) = Contractor of the grant sponsors = Dual responsibility

9. Rights & obligations of the PI for the trial • Preparation • Conduct • Administration

10. Role of the PI BEFORE the trial First decision: accept or decline the trial! Prerequisites for the selection of sites: • Personal network • Experience with the centers • Team of the particular site (Investigator & research nurse)

11. Most important at the start • inclusioncriteria • exclusioncriteria

12. OUTLINE What do I want so share with you? • Definition of the PI • Personal experience • Your needs

13. Rights & obligations of the PI for the trial • Preparation • Conduct • Administration

14. Essential infrastructure of a site • MD (withtrialexperience) • Study nurse • Study coordinator • Administration Support • Space and time foroutpatientclinic

15. VIVIT TEAM

16. Main role of the PI DURING the trial • Solution of problems with recruitment • Proposalforrevisionofinclusioncriteria • Exchange with PIs fromotherregions • Regular telephoneconferences • Personal meetings • Share tipsand tricks withsubinvestigators(SI) • Motivation ofsites • Tribulate…

17. Duties of the local PI DURING the trial • Solution of problems with recruitment • Trouble shooting within the center – weekly meetings • Motivation of reluctant GPs • Improve cooperation between divisions

18. Rights & obligations of the PI for the trial • Preparation • Conduct • Administration

19. Duties of the local PI DURING the trial • Prevent GCP violations

20. Duties of the local PI DURING the trial • Prevent GCP violations • Check/sign informed consent sheets • Check/sign CRFs (case report forms) • Report SAEs and endpoints within 24 hours • Read/sign safety report forms • Take ample time for monitor visits • Be prepared for audits (sponsor, gouvernment)

21. Rights & obligations of the PI for the trial: SUMMARY • Preparation • Conduct • Administration

22. OUTLINE What do I want so share with you? • Definition of the PI • Personal experience • Your needs

23. Prerequisites for the young trialist • Enthusiasm • Good time management • GCP knowledge • Long-term commitment • Patience • Straightforwardness

24. Range of priorities for the young researcher:A good example 1. Time for research 2. Clinical resident work 3. Outpatient clinic 4. Emergency medicine 5. Leisure time

25. Range of priorities for the young researcher:A bad example 1. Emergency medicine 2. Outpatient clinic 3. Clinical resident work 4. Leisure time 5. Time for research

26. Advantages and Disadvantages of Randomized Clinical Trials (RCT‘s) PRO • Precisejudgementof an intervention • In a preciselydefinedpopulation • Prospective design • Minimizes (but not eliminates) bias • Allowsfor meta-analysis CONTRA • Expensive • Time consuming • Dependscritically on patientinclusion

27. From Dream to Nightmare: • What makes a Trial Useless? • Verysimilartrialalreadydoneandconclusive • Necessityfor extreme patientnumbers • Randomizationunethical • Main questioncannotbeanswered by a RCT

28. An Example

29. ODYSSEY Phase 3 Programm Fourteen global Phase 3 trials including >23 500 patients across >2000 study centres HeFH population HC in high CV-risk population Additional populations Add-on to max tolerated statin (± other LLT) Add-on to max tolerated statin (± other LLT) ODYSSEY MONO (NCT01644474; EFC11716) Patients on no background LLTs LDL-C ≥100 mg/dL n=103; 6 months ODYSSEY COMBO I (NCT01644175; EFC11568) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=316; 12 months ODYSSEY FH I (NCT01623115; EFC12492) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=486; 18 months ODYSSEY ALTERNATIVE (NCT01709513; CL1119) Patients with defined statin intolerance LDL-C ≥70 mg/dL ORLDL-C ≥100 mg/dL n=314; 6 months †ODYSSEY COMBO II (NCT01644188; EFC11569) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=720; 24 months ODYSSEY FH II (NCT01709500; CL1112) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=249; 18 months ODYSSEY CHOICE I (NCT01926782; CL1308) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=700; 12 months ODYSSEY CHOICE II (NCT02023879; EFC13786) Patients not treated with a statin LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=200; 6 months ODYSSEY HIGH FH (NCT01617655; EFC12732) LDL-C ≥160 mg/dL n=107; 18 months ODYSSEY OLE (NCT01954394; LTS 13463) Open-label study for FH from EFC 12492,CL 1112, EFC 12732 or LTS 11717 n≥1000; 30 months ODYSSEY LONG TERM (NCT01507831; LTS11717) LDL-C ≥70 mg/dL n=2341; 18 months ODYSSEY OPTIONS I (NCT01730040; CL1110) Patients not at goal on moderate-dose atorvastatin LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=355; 6 months ODYSSEY OUTCOMES (NCT01663402; EFC11570) LDL-C ≥70 mg/dL n=18 000; 64 months ODYSSEY OPTIONS II (NCT01730053; CL1118) Patients not at goal on moderate-dose rosuvastatin LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=305; 6 months †For ODYSSEY COMBO II other LLT not allowed at entry.

30. Our Experiences: ODYSSEY-Trial

31. Odyssey Study: Study Update

32. High dropouts after screening: • Adequatelycontrolledlipidlevels • Patient: • Unwillingtosubcutaneousinjections • Right after theacuteevent (ACS) • Tiredofhospitalvisits • Local MD (GP) refused: Objectivesofstudyunknown • After Randomization • Low dropouts (0 at oursite) • Screened 34, Randomized 7, Drop outs 0 OdysseyStudy: 1 Year Experience

33. ESC Working Group Meeting „Cardiovascular Pharmacotherapy“ - How to run a trial efficiently, May 29, 2015 The Role of the PI: Keys to Success, Perils and Tribulations Heinz Drexel, MD, FESC, FAHA Department of Medicine and Cardiology & VIVIT Institute at the Academic Teaching Hospital Feldkirch, A Private University of the Principality of Liechtenstein, Triesen, FL Drexel University College of Medicine, Philadelphia, PA, USA